KR0156275B1 - Process for preparation of ceftazidime pentahydrate - Google Patents

Abstract

The present invention provides an improved process for the preparation of ceftazidime pentahydrate from ceftazidime, the method of which is (6R, 7R) -7-[(Z) of the following general formula (4) ) -2- (2-tritylaminothiazol-4-yl) -2- (2-butoxycarbonylprop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl)- (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy of the following general formula (4) from 3-cefe-4-carboxylate N-N-dimethylformamide solvate of prop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate was prepared, and this compound was distilled water. Or neutralizing with an acid or organic or inorganic base after dissolving in a mixed solvent of distilled water and a water-soluble organic solvent.

(Wherein DMF is N, N-dimethylformamide and X represents the mole number of N, N-dimethylformamide.)

Description

Method for preparing ceftazidime pentahydrate

The present invention relates to an improved process for the preparation of crystalline ceftazidime pentahydrate of the general formula (1) below which enhances the stability and purity of ceftazidime, a colorless crystalline form useful as an antibiotic.

The chemical name is (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3 A method for preparing ceftazidime pentahydrate, a pentahydrate of-(1-pyridiniummethyl) -3-cepm-4-carboxylate, is described in Korean Patent Publication No. 84-1776.

Briefly describing the manufacturing method of Korean Patent Publication No. 84-1776, (6R, 7R) -7- [produced by Korean Patent Publication Nos. 83-835 and 83-836, as shown in Reaction Scheme 1 below. (Z) -2- (2-tritylaminothiazol-4-yl) -2- (2-butoxycarbonylprop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl ) -3-cepem-4-carboxylate (formula 2) is dissolved in formic acid and concentrated hydrochloric acid is added to (6R, 7R) -7-[(Z) -2- (2-aminothiazole-4- Yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate bishydrochloride salt (= ceptazidime Dihydrochloride) (General Formula 3) and neutralize it with a base in water or a mixed solvent of water and organic solvent, or neutralize the liquidity of the solution, and then adjust the pH to 2.5-4.5 using acid again. Crystallization of Ceftazidime Pentahydrate of Formula 1 It features.

On the other hand, in order to crystallize ceftazidime in the form of ceftazidime pentahydrate, the purity of the material used as an intermediate should be very good, and the solution is well crystallized when there are few ionic salts.

The present inventors have diligently researched to provide a method for producing ceftazidime pentahydrate having high stability and purity in a process that is easier to manufacture. The use of dim N, N-dimethylformamide solvate has found that the above object can be achieved and the present invention has been completed.

Accordingly, an object of the present invention is (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazole) -2- (2-t-butoxycarbonyl) Ceftazidim dimethylformamide solvate of the following general formula (4) was prepared from 2-propoxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate. And dissolving it in water or a mixed solvent of water and a water-soluble organic solvent, and then crystallizing it using an acid, an organic or inorganic base, to provide a method for producing ceftazidime pentahydrate of the following general formula (1). will be.

Hereinafter, the present invention will be described in more detail.

According to the present invention, the intermediate of the process for obtaining the ceftazidime pentahydrate crystals from ceftazidime is (6R, 7R) -7-[(Z) -2- ( 2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate N, N-dimethylformamide solvate (seftazidim dimethylformamide solvate) is prepared and dissolved in water or a mixed solvent of water and water-soluble organic solvent using an acid or an alkali to dissolve the ionic compound in the solution. The concentration can be minimized to effectively crystallize ceftazidime pentahydrate.

The method according to the present invention is shown as a reaction diagram as follows.

In the method of the present invention as described above, the dimethylformamide solvate of ceftazidime used as an intermediate is a novel substance, which is easier to handle during operation than ceftazidime dihydrochloride, and is very sensitive to the influence of humidity in the atmosphere. It is stable and excellent in thermal stability as well as the production of ceftazidime pentahydrate using this compound has the advantage of increased yield and reduced cost compared to the prior art.

Hereinafter, the present invention will be described in more detail.

Known methods, for example, (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazole) -2 prepared by Korean Patent Publication No. 83-835 or 83-836 -(2-t-butoxycarbonyl-2-propoxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate Formula 2) The reaction mixture was reacted in a mixed solution of formic acid and hydrochloric acid to remove the t-butyl group of the trityl group, and the solution was filtered to remove the triphenylcarbinol. Subsequently, a certain amount of N, N-dimethylformamide is added to the filtrate and crystallized in acetone to give a colorless crystalline compound of the following general formula (4).

(Wherein DMF is N, N-dimethylformamide and X is a number between 1.0 and 2.0.)

After drying the crystals, it was confirmed that the dimethyl formamide solvate of ceftazidim was found through nuclear magnetic resonance spectra, high pressure liquid chromatography, infrared spectra and gas chromatogram.

The dimethylformamide solvate of ceftazidime prepared in this manner is dissolved in an appropriate amount of distilled water or a mixed solvent of an appropriate amount of distilled water with an appropriate amount of a water-soluble organic solvent, and then the pH is 3.75 using an inorganic or organic base or an acid. If it is stirred while adjusting, crystals will precipitate. Subsequently, the pH is adjusted to about 3.5 to 4.0, cooled under ice-cooling, filtered, washed with distilled water and acetone, and dried to produce high purity ceftazidime pentahydrate.

Examples of the water-soluble organic solvent used in the reaction of the present invention include lower alcohols having 1 to 5 carbon atoms, acetonitrile, dimethylformamide, dimethyl sulfoxide and acetone, and preferably acetone and methyl alcohol. As the inorganic base, sodium hydroxide, potassium hydroxide, ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium carbonate can be used, but preferably sodium hydroxide or ammonia is used. Organic bases include lower primary amines such as methylamine and ethylamine, lower secondary amines such as dimethylamine and diethylamine, lower tertiary amines such as triethylamine, sodium methoxide, potassium methoxide, sodium acetate, 2 A metal alkoxide such as sodium ethylhexanoic acid may be used, but preferably sodium acetate or sodium methoxide is used.

Hereinafter, the present invention will be described in detail with reference to Examples. The scope of the present invention is not limited by these Examples.

Example 1

13.2 g of phosphorus pentachloride was added to 200 ml of methylene chloride, and the temperature was cooled to -15 占 폚, to which [(Z) -2- (2-tritylaminothiazol-4-yl) -2- (2-butoxy 32.8 g of carbonyl-2-propoxyimino) acetic acid were added. The reaction mixture was stirred at 0-5 ° C. for 1 hour, then cooled to −40 ° C. and 12.8 g of triethylamine was added over 5 minutes. 150 ml of water was added thereto, stirred at 0-5 ° C. for 5 minutes, and separated, and 23 g of 7- (1-pyridiniummethyl) -3-cef-4-carboxylate iodide was added with 150 ml of dimethylformamide and acetonitrile. 24.7 g of triethylamine was added to the 50 mL solution, and the solution was added to the solution cooled to −40 ° C. for 15 minutes and then reacted for 2 hours while maintaining the temperature of −20 to 25 ° C. Then, 400 ml of water was added thereto, stirred for 5 minutes, and the organic layer was separated. Then, 200 ml of water was added thereto, stirred for 5 minutes, and the organic layer was separated. 15 g of anhydrous sodium sulfate was added to the separated organic layer to remove water from the organic layer, filtered, and then concentrated under reduced pressure. 100 ml of methylene chloride and 150 ml of dimethyl acetamide were added thereto, stirred overnight, and then filtered. %) Was obtained.

Example 2

(6R, 7R) -7-[(Z) -2-tritylaminothiazol-4-yl) -2- (2-t-butoxycarbonylprop-2-oxyimino) acetamido]- 30 g of 3- (1-pyridiniummethyl) -3-cepem-4-carboxylate was dissolved in 40 ml of formic acid (98%), and then 14.5 ml of concentrated hydrochloric acid was added with stirring at room temperature, followed by reaction at room temperature for 3 hours. The triphenyl carbinol produced by filtration was removed and washed with an appropriate amount of formic acid (98%). 60 ml of N, N-dimethylformamide and 150 ml of acetone were added thereto, solidified, stirred for 2 hours at room temperature, and filtered to obtain 19.8 g (90%) of the title compound.

Example 3

7.0 g of ceftazidime dimethylformamide solvate of Example 1 was dissolved in 17.5 mL of distilled water and stirred while adjusting to pH 3.75 by slowly adding 2N-sodium hydroxide solution. If well crystallized, the pH, which was raised to 4.3, was maintained at 3.75 again using 1N hydrochloric acid. The suspension was ice-cooled, the title compound was filtered off, washed with 10 ml of distilled water and acetone and dried at room temperature for 1 hour in an air oven to give 6.1 g of crystalline solid.

Example 4

7.0 g of ceftazidime dimethylformamide solvate of Example 2 was dissolved in 17.5 mL of distilled water and stirred while adjusting to pH 3.75 by slowly adding 50% sodium acetate solution. When the crystallization was good, the pH, which was raised to 4.4, was maintained at 3.75 again using 1N hydrochloric acid. The suspension was cooled under ice cooling, the title compound was filtered off, washed with 10 milliliters of distilled water and acetone and dried at room temperature for 1 hour in an air oven to yield 6.0 grams of crystalline solid.

Nuclear Magnetic Resonance Spectrum: Same as the compound of Example 3

High pressure liquid chromatogram: 97.9% (relative to standard compound)

Moisture content (Kar Fischer method): 14.1%

Example 5

3.0 kg of ceftazidime dimethylformamide solvate of Example 2 was dissolved in 8.75 L of distilled water and basified to pH 6 with 2N-sodium hydroxide solution (approximately 6.5 L) while maintaining at about 14-15 ° C. The sodium salt solution thus obtained was sterilized by passing through a membrane filter (0.22㎛ pore size) and then washed with distilled water (4 L). Subsequent manipulations were also performed aseptically. The filtered solution was adjusted to pH 3.75 with 1N hydrochloric acid (approximately 3.0 L), seeded with 1.0 g of the title compound sterilized at 14-15 ° C. and stirred until crystallization was complete.

The mixture was kept at 14-15 ° C. overnight without stirring. Essentially the pH was readjusted back to 3.75. The title compound was collected by filtration with a fiberless nylon mesh, washed and washed with ice cold water for injection (approximately 5.0 L) and sterile acetone (approximately 5.0 L).

The product was dried in a sterile filtered nitrogen stream until the acetone content was less than 0.2% to give 2.6 Kg of the title compound.

Nuclear Magnetic Resonance Spectrum: Same as the compound of Example 3

Fine liquid chromatogram: 97.8% (compared to standard compound)

Moisture content (Kar Fischer method): 13.8%

Claims (2)

(6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (2-butoxycarbonylprop-2- of the following general formula (2) Oxiimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate of (6R, 7R) -7-[(Z) -2- of formula (4) Of (2-iminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamino] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate N, N-dimethylformamide solvate is prepared, and the compound is dissolved in distilled water or a mixed solvent of distilled water with a water-soluble organic solvent and neutralized with an acid or an organic or inorganic base. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- ( Method for preparing 1-pyridiniummethyl) -3-cepem-4-carboxylate pentahydrate. (Wherein DMF is N, N-dimethylformamide and X represents the number of moles of N, N-dimethylformamide) The (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (2-carboxyprop) of claim 1, wherein 2-oxyimino) acetamido] -3- (1-pyridiniummethyl) -3-cepem-4-carboxylate molar equivalent of dimethylformamide of N, N-dimethylformamide solvate of 1.0 to 2.0 Manufacturing method characterized in that.